HGNC Approved Gene Symbol: TDP1
SNOMEDCT: 765091006;
Cytogenetic location: 14q32.11 Genomic coordinates (GRCh38) : 14:89,954,968-90,044,764 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q32.11 | ?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 | 607250 | Autosomal recessive | 3 |
Topoisomerases are involved in the replication and readout of the genome. They work by breaking the DNA backbone, allowing a topologic change and the creation of a covalent protein-DNA intermediate union, and resealing the break. This last step is crucial and requires hydrolysis of the DNA-protein bond by a conserved tyrosyl-DNA phosphodiesterase, or TDP (summary by Pouliot et al., 1999).
By analysis of yeast with disrupted genes after chemical mutagenesis, EST database searching, and 5-prime RACE, Pouliot et al. (1999) identified sequences encoding the C- and N-terminal ends of human TDP1. The deduced 608-amino acid protein is highly conserved in eukaryotes, but not, apparently, in prokaryotes. The authors suggested that the gene is a potential tool to enhance the efficacy of anticancer drugs by repairing topoisomerase lesions.
By sequence analysis, Interthal et al. (2001) showed that TDP1 contains 2 unusual HKD signature motifs, typical of members of the phospholipase D (PLD; see 602382) superfamily. Mutation analysis determined that the invariant histidines and lysines of these motifs are essential for TDP1 activity. Interthal et al. (2001) concluded that the hydrolytic reaction catalyzed by TDP1 occurs by the phosphoryl transfer chemistry that is common to all members of the PLD superfamily.
Takashima et al. (2002) reviewed the function of TDP1. TDP1 is involved in repairing covalent topoisomerase I-DNA complexes and is a member of the phospholipase D superfamily. To modulate the topologic changes induced during DNA replication and transcription, topoisomerase I (TOP1; 126420) transiently breaks a DNA strand and forms a covalent linkage between the active-site tyrosine and the 3-prime phosphate of the broken DNA strand; the strand is subsequently relegated by nucleophilic attack of the 5-prime hydroxyl on this phosphodiester bond. But under certain conditions, nucleophilic attack of the 5-prime hydroxyl does not occur and the topoisomerase I forms a stalled covalent complex with the DNA. Efficient repair of these stalled complexes requires functional TDP1 to catalyze the hydrolysis of the phosphodiester bond between the tyrosine residue and the DNA 3-prime phosphate.
El-Khamisy et al. (2005) showed that in human cells TDP1 is required for repair of chromosomal single-strand breaks arising independently of DNA replication from abortive topoisomerase-1 (TOP1; 126420) activity or oxidative stress. They reported that TDP1 is sequestered into multiprotein single-strand break repair (SSBR) complexes by direct interaction with DNA ligase III-alpha (600940) and that these complexes are catalytically inactive in lymphoblastoid cell lines derived from patients with spinocerebellar ataxia with axonal neuropathy (SCAN1; 607250). El-Khamisy et al. (2005) concluded that their data identified a defect in SSBR in a neurodegenerative disease, and implicated this process in the maintenance of genetic integrity in postmitotic neurons.
Davies et al. (2002) resolved the crystal structure of TDP1 at the 1.69-angstrom level. They determined that TDP1 is a monomer composed of 2 similar domains, each contributing his, lys, and asn residues to form a single active site. The structure confirmed that TDP1 has a catalytic mechanism similar to members of the PLD superfamily. Davies et al. (2002) proposed that the structure indicates how the unusual protein-DNA substrate binds and gives insight into the nature of the substrate in vivo.
In a multigenerational consanguineous Saudi Arabian family with autosomal recessive spinocerebellar ataxia with axonal neuropathy-1 (SCAN1; 607250), Takashima et al. (2002) identified a homozygous missense mutation in the TDP1 gene (H493R; 607198.0001). The mutation occurred in the active site of the enzyme, and protein modeling predicted that it would disrupt the symmetric structure of the active site. Takashima et al. (2002) proposed that loss-of-function mutations in TDP1 may cause SCAN1 either by interfering with DNA transcription or by inducing apoptosis in postmitotic neurons.
In a multigenerational consanguineous Saudi Arabian family in which 9 members had autosomal recessive spinocerebellar ataxia with axonal neuropathy-1 (SCAN1; 607250), Takashima et al. (2002) identified a homozygous c.1478A-G transition in the TDP1 gene, resulting in a his493-to-arg (H493R) substitution at a conserved residue in the active site of the enzyme. The mutation was found by linkage analysis followed by candidate gene sequencing. The presenting symptom of this disorder was disturbance of gait in the teen years. There were signs of peripheral axonal motor and sensory neuropathy and distal muscular atrophy with pes cavus and steppage gait. All affected individuals had normal intelligence.
Davies, D. R., Interthal, H., Champoux, J. J., Hol, W. G. J. The crystal structure of human tyrosyl-DNA phosphodiesterase, Tdp1. Structure 10: 237-248, 2002. [PubMed: 11839309] [Full Text: https://doi.org/10.1016/s0969-2126(02)00707-4]
El-Khamisy, S. F., Saifi, G. M., Weinfeld, M., Johansson, F., Helleday, T., Lupski, J. R., Caldecott, K. W. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature 434: 108-113, 2005. [PubMed: 15744309] [Full Text: https://doi.org/10.1038/nature03314]
Interthal, H., Pouliot, J. J., Champoux, J. J. The tyrosyl-DNA phosphodiesterase Tdp1 is a member of the phospholipase D superfamily. Proc. Nat. Acad. Sci. 98: 12009-12014, 2001. [PubMed: 11572945] [Full Text: https://doi.org/10.1073/pnas.211429198]
Pouliot, J. J., Yao, K. C., Robertson, C. A., Nash, H. A. Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes. Science 286: 552-555, 1999. [PubMed: 10521354] [Full Text: https://doi.org/10.1126/science.286.5439.552]
Takashima, H., Boerkoel, C. F., John, J., Saifi, G. M., Salih, M. A. M., Armstrong, D., Mao, Y., Quiocho, F. A., Roa, B. B., Nakagawa, M., Stockton, D. W., Lupski, J. R. Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nature Genet. 32: 267-272, 2002. [PubMed: 12244316] [Full Text: https://doi.org/10.1038/ng987]